Perinatal Hypoxic-Ischemic Encephalopathy

Figure 1

Proposed pathogenesis of hypoxic-ischemic encephalopathy. The central roles for ATP depletion, membrane depolarization, glutamate-mediated excitotoxicty, and voltage-dependent and glutamate-activated Ca²⁺ channels are apparent. An initial decrease in high-energy phosphates can result in an acute influx of Na⁺, Cl⁻, and water with consequent cell death (necrosis) in the severe insult, whereas in less severe insult, it causes membrane depolarization followed by a cascade of excitotoxicity and oxidative stress leading to a delayed cell death, principally apoptosis. Persistent membrane depolarization results excessive presynaptic glutamate release, reversal of glutamate transport in glia and neural terminals, and activation of NMDA and immature (GluR2 deficiency) AMPA receptors with profound Ca²⁺ influx with a series of Ca²⁺-mediated cascades to cell death. The deleterious effects of cytosolic Ca²⁺ are multiple, including degradation of cellular lipids by activation of phospholipase and of cellular DNA by activation of nucleases and enhancement of generation of free radicals and nitric oxide (NO) by increase of nitric oxide synthase (NOS) [7, 8, 26]. AMPA: α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; ER: endoplasmic reticulum; mGlu: metabotropic glutamate; NMDA: N-methyl-D-aspartic acid; NOS: nitric oxide synthase; VDCC: voltage-dependent calcium channels